What is HMB (beta-Hydroxy beta-Methylbutyrate)?

What is HMB (Beta-Hydroxy Beta-Methylbutyrate)?

HMB is a metabolite of the essential amino acid leucine that functions as an anticatabolic agent to reduce muscle protein breakdown and preserve muscle mass, particularly during periods of physical stress, immobilization, or disease. 1, 2

Mechanism of Action

HMB works through multiple pathways to preserve and build muscle:

• Reduces protein degradation by inhibiting the ubiquitin-proteasome pathway, which is the primary system responsible for breaking down muscle proteins 2
• Enhances protein synthesis through activation of the mTOR (mammalian target of rapamycin) pathway, which stimulates muscle protein production 2, 3
• Improves sarcolemma integrity, protecting muscle cell membranes from damage during exercise or stress 2
• Decreases cell apoptosis (programmed cell death) in muscle tissue 2
• Stimulates the growth hormone/insulin-like growth factor-1 (GH/IGF-1) axis, promoting anabolic effects 2
• Enhances muscle stem cell proliferation and differentiation, supporting muscle repair and growth 2

Clinical Applications and Evidence Quality

Perioperative and Bedrest Settings

In healthy volunteers undergoing 10 days of bedrest, HMB supplementation significantly reduced muscle loss and increased muscle mass gain during the 8-week rehabilitation phase, while also preserving muscle strength. 4 This represents one of the strongest applications with direct evidence of benefit on clinically meaningful outcomes.

Frailty and Pre-Frailty

• High protein oral nutrition shakes supplemented with HMB (HP-HMB) improved physical function and muscle mass in patients with pre-frailty 4
• When combined with resistance training, protein supplements with HMB appear to enhance training benefits 4

Hospitalized Medical Patients

• The NOURISH trial demonstrated that high protein HMB oral nutritional supplements (ONS) significantly decreased 90-day post-discharge mortality (4.8% vs 9.7%; RR 0.49,95% CI 0.27-0.90, p=0.018) in malnourished inpatients 4
• This intervention was cost-effective and helped maintain muscle mass during hospital stay 4
• In COPD patients specifically, HMB ONS increased handgrip strength from discharge to 30 days (1.56 kg vs 0.34 kg, p=0.0413) and body weight 4

Critical Care

HMB shows promise for muscle preservation in ICU patients, but recent evidence is mixed—two recent ICU studies showed no difference in muscle loss 4, 3. More research is needed in broader ICU populations 4

Cancer Cachexia

The evidence for HMB in cancer cachexia is inconsistent and insufficient to make a general recommendation. 4, 3

• ESPEN guidelines state there is insufficient consistent clinical data to recommend HMB for improving fat-free mass in cancer patients 4, 3
• A large RCT in 472 cachectic cancer patients failed due to poor compliance (only 37% completed the protocol), with no significant differences observed 4
• Some smaller studies showed promise when HMB was combined with arginine and glutamine, but compliance remains a major barrier 4

Dosing and Safety

• The standard dose is 3 grams per day, which can be routinely recommended to maintain or improve muscle mass and function 1
• The safety profile of HMB is unequivocal—it is well-tolerated with no significant adverse effects reported 1

Clinical Context: When HMB Works Best

HMB is most effective in specific situations:

• Untrained individuals exposed to strenuous exercise show the greatest benefit 5
• Trained individuals exposed to periods of high physical stress (injury, surgery, immobilization) benefit significantly 5
• Older adults, particularly when combined with exercise, show optimal effects on muscle growth and strength 5
• Hospitalized malnourished patients demonstrate mortality benefit and functional improvements 4

Important Caveat

HMB appears less effective in strength-trained athletes, likely because training adaptation already suppresses proteolysis, blunting HMB's anticatabolic effects 5. Additionally, several studies suggest that HMB supplementation does not produce anabolic effects in healthy, non-exercising subjects 5.

Practical Recommendations

For clinical use, consider HMB supplementation in:

1. Perioperative patients at risk for prolonged bedrest or immobilization 4
2. Malnourished hospitalized patients, particularly older adults with multiple comorbidities 4
3. Frail or pre-frail older adults, especially when combined with resistance exercise programs 4
4. Patients with COPD or cardiovascular disease who are hospitalized and at risk for functional decline 4

Do not routinely recommend HMB for cancer cachexia patients given inconsistent evidence and compliance challenges, though individual trials may be considered in research settings 4, 3.